Regio- and Stereoselective Synthesis of Spiropyrrolizidines and

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Regio- and Stereoselective Synthesis of Spiropyrrolizidines and Piperazines through Azomethine Ylide Cycloaddition Reaction Saoussen Haddad, Sarra Boudriga, Francois Porzio, Armand Soldera, Moheddine Askri, Michael Knorr, Yoann Rousselin, Marek M. Kubicki, Christopher Golz, and Carsten Strohmann J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01399 • Publication Date (Web): 20 Aug 2015 Downloaded from http://pubs.acs.org on August 24, 2015

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The Journal of Organic Chemistry

Regio- and Stereoselective Synthesis of Spiropyrrolizidines and Piperazines through Azomethine Ylide Cycloaddition Reaction Saoussen Haddad,†,‡ Sarra Boudriga,† François Porzio,‡ Armand Soldera,‡ Moheddine Askri,†,* Michael Knorr,§ Yoann Rousselin,∥ Marek M. Kubicki,∥ Christopher Golz,⊥ Carsten Strohmann⊥ †

Laboratoire de Chimie Hétérocyclique, Produits Naturels et Réactivité/ LCHPNR,

Département de Chimie, Faculté des Sciences de Monastir, 5000 Monastir, Tunisie ‡

Département de Chimie, Centre Québécois sur les matériaux fonctionnels, Université de

Sherbrooke, Sherbrooke, Québec, Canada, J1K 2R1 §

Institut UTINAM - UMR CNRS 6213, Université de Franche-Comté, 16 Route de Gray, F-

25030 Besançon, France ∥Institut

de Chimie Moléculaire - UMR CNRS 6302, Université de Bourgogne, 9 Avenue A.

Savary, F-21078 Dijon, France ⊥Technische

Universität Dortmund, Anorganische Chemie, Otto-Hahn-Strasse 6, 44221

Dortmund, Germany

*e-mail: [email protected] ; phone: +216 98676187

Abstract Graphics

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ABSTRACT A series of original spiropyrrolizidine derivatives has been prepared by a one-pot threecomponent [3+2] cycloaddition reaction of (E)-3-arylidene-1-phenyl-pyrrolidine-2,5-diones, L-proline and the cyclic ketones 1H-indole-2,3-dione (isatin), indenoquinoxaline-11-one and acenaphthenequinone. We disclose an unprecedented isomerization of some spiroadducts leading to a new family of spirooxindolepyrrolizidines. Furthermore, these cycloadducts underwent retro-1,3-dipolar cycloaddition yielding unexpected regioisomers. Upon treatment of the dipolarophiles with in situ generated azomethine ylides from L-proline or acenaphthenequinone, formation of spiroadducts and unusual polycyclic fused piperazines through a stepwise [3+3] cycloaddition pathway is observed. The stereochemistry of these N-heterocycles has been confirmed by several X-ray diffraction studies. Some of these compounds exhibit extensive hydrogen bonding in the crystalline state. To enlighten the observed regio- and stereoselectivity of the [3+2] cycloaddition, calculations using the DFT approach at the B3LYP/6-31G(d,p) level were carried out. It was found that this reaction is under kinetic control.

INTRODUCTION Synthesis of derivatives of natural products is particularly attractive, especially if they ultimately lead to biological activities. In this context, the potential of pyrrolizidine derivatives was not exploited sufficiently. These latter have attracted a great deal of interest because of their frequent occurrence in natural products and their significant biological activities.1,2 In particular, multifunctional polycyclic spiropyrrolizidines contain a privileged heterocyclic skeleton that is found in a large family of synthetic compounds exhibiting versatile bioactivities, such as antimycobacterial,3 antitumor,4 antimicrobial,5 antibacterial,6 antifungal7 and antiviral8 properties. The spiropyrrolizidine unit also occurs in several natural


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products, such as peteropodine, isopeteropodine, mitraphylline9 and spirotryprostatin A10 (Figure 1). Efficient synthesis of such molecules is thus of particular relevance, we therefore propose in this report a new one-pot synthesis of spiropyrrolizidines derivatives.

Figure 1. Examples of Naturally Occurring Spiropyrrolizidine-Derived Alkaloids.

Driven by thorough investigation of the biological activities of this class of compounds, much attention has been focused on the development of efficient methodologies for the preparation of structurally diverse spiropyrrolizidines. The actual multicomponent 1,3-dipolar cycloaddition of electron-deficient alkenes with azomethine ylides generated in situ via decarboxylative condensation of cyclic ketones and L-proline provides a very effective tool to access spiropyrrolizidine containing compounds.11 Its process simplicity, mild reaction conditions, atomic economy and extension of the scope of substrates made it a current route in combinatorial chemistry. On the other hand, the pyrrolidine-2,5-dione scaffold is a central component of numerous alkaloids, as well as a great variety of synthetic compounds endowed with diverse bioactivities, including anticonvulsant,12 antimycobacterial13 and antidepressant properties.14

Recently,

we

have

reported

the

synthesis

of

new

functionalized

spirooxindolepyrrolidines and dispiropyrrolothiazoles incorporating the pyrrolidine-2,5-dione motif. Some representative molecules exhibiting antibacterial, antifungal, antimalarial and antimycobacterial activities are shown in Figure 2.15 Prompted by the synthetic interest and applications of spiropyrrolizidine and pyrrolidine-2,5-dione skeletons as part of our research



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on N-spiroheterocycles,16 we describe herein the synthesis of a novel series of spiropyrrolizidines via one-pot multicomponent 1,3-dipolar cycloaddition reaction of (E)-3arylidene-1-phenyl-pyrrolidine-2,5-diones with azomethine ylides.17 The latter have been generated in situ by reaction of various cyclic ketones and L-proline.

Figure 2. Representative Examples of Bioactive Synthesized Compounds Incorporating a Pyrrolidine-2,5-dione Motif.

Cycloaddition reaction of exocyclic α,β-unsaturated ketones with azomethine ylide derived from L-proline and isatin exclusively leads to dispiropyrrolizidine with two adjacent spirocarbons, whilst formation of the other regio- and stereoisomers has never been reported (Scheme 1).11 We thus describe for the first time the formation of the hitherto unknown regioisomer.

Moreover,

spirooxindolepyrrolizidines

we

revealed

(Scheme

1).

an

unprecedented To

our

epimerization

knowledge,

such

of regio-

some and

diastereodivergent cycloadditions have not been reported yet. To support our findings we carried out calculations at the quantum level. Theoretical investigations on the reaction of


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acyclic alkenes with azomethine ylides derived from L-proline and isatin have been reported recently.18 However, there are no reports on the cycloaddition of exocyclic alkenes with this type of 1,3-dipole. Density Functional Theory (DFT) was thus used to rationalize the unusual regio- and diastereoselectivity of this kind of reaction.

Scheme 1. Profile of the 1,3-Dipolar Cycloaddition of Exocyclic α,β-Unsaturated Ketones across Azomethine Ylides Derived from L-proline and Isatin. “•” Denotes a Spiranic Carbon.

RESULTS AND DISCUSSION Three-component Synthesis of the Spiropyrrolizidines 4-6. To optimize the reaction conditions, the three-component reaction of isatin 1a, L-proline 2 and (E)-3-arylidene-1phenylpyrrolidine-2,5-dione 3d (Ar = p-ClC6H4) was chosen as a model (Table 1). In order to evaluate both the effect of solvent and temperature, the reaction was conducted at different temperatures in acetonitrile and methanol as reaction media. The collected data presented in entries 1-6 of Table 1 indicate that the regio- and stereoselectivity of this reaction are both solvent- and temperature-dependent. This optimization study revealed that the best results were obtained by refluxing the reaction mixture in methanol for 0.5 hour, providing spirooxindolepyrrolizidine 4d with an excellent yield (85%) (Table 1, entry 4). However, a



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prolongation of the reflux time (24 h) afforded an isomeric mixture of 4d:5d:6d in a 57:24:19 ratio (Table 1, entry 5). This finding is in contrast to the commonly observed regio- and stereoselectivity outcome in these type of 1,3-dipolar cycloaddition reactions.11, 17

Table 1. Reaction Conditions Employed for the Synthesis of Spiroyrrolizidines 4d, 5d and 6da

Entry 1 2 3 4 5 6

Solvent CH3CN CH3CN CH3CN MeOH MeOH MeOH

T (°C) 80 80 24 64 64 25

Time (h) 2 36 5 0.5 24 24

Yield (%)b 70 70 65 85 85 NRd

Ratioc4d/5d/6d 100 : 00 : 00 72 : 18 : 10 100 : 00 : 00 100 : 00 : 00 57 : 24 : 19 -

a The reactions were carried out with 1a (0.5 mmol), 2 (0.75 mmol) and 3d (0.5 mmol) in solvent (10 mL). bOverall yields after isolation of the products by column chromatography. cRelative ratios were determined by 1H NMR from the crude reaction mixture. dNo reaction due to insufficient solubility.

Having established suitable reaction conditions (Table 1, entry 5), we tried to extend the scope of this reaction using a series of different p-aryl substituted dipolarophiles 3. This was done with the objective to examine the influence of the electronic effects exerted by the substituent at the p-position of the aryl group of imides 3 on the outcome of the reaction (Table 2). As shown in Table 2, reaction of imides 3a-e yielded the two regioisomers 4 and 5 along with the diastereoisomers 6 (Table 2, entries 1-5). Independently of the M-effect of the p-aryl substituent, isomer 4 is the dominant one in all entries. The reaction mixture has been separated by column chromatography.


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Table 2. Synthesis of Spiropyrrolizidines 4-6 via Three-Component Reaction of of Isatin 1a, L-proline 2 and Dipolarophiles 3a

Entry 1 2 3 4 5

Ar C6H5 p-MeC6H4 p-MeOC6H4 p-ClC6H4 p-FC6H4

Products 4a + 5a + 6a 4b + 5b + 6b 4c + 5c + 6c 4d + 5d + 6d 4e + 5e + 6e

Yields (%)b 82 90 92 85 91

Ratioc4/5/6 76 : 13 : 11 65 : 18 : 17 71 : 18 : 11 53 : 28 : 19 55 : 30 : 15

a The reactions were carried out with 1a (0.5 mmol), 2 (0.75 mmol) and 3 (0.5 mmol) in methanol (10 mL) at 64 °C for 24 h. b Overall yields after isolation of the products by column chromatography. cRelative ratios were determined by 1H NMR from the crude reaction mixture.

Spectroscopic and Crystallographic Characterization of the Isomeric Cycloadducts. The structure and the relative configuration of the isomeric spiropyrrolizidines resulting from the cycloaddition was deduced in solution from their NMR data and in the solid state from three X-ray structure determinations performed on cycloadducts 4e, 5d and 6d. Selected chemical shift values and NOE correlation of spiropyrrolizidines 4d, 5d and 6d are indicated in Figure 3. The 1H NMR spectra of 4d and 6d show two mutually coupled doublets centered at 2.68 ppm and 3.31 ppm (J = 18.7 Hz for 4d and 18.1 Hz for 6d) corresponding to the diastereotopic 4’-CH2 group. Furthermore, the protons H-4 usually appears as a doublet at δ 4.05 and 5.05 ppm in 4d and 6d respectively. Their coupling constants of approximately 9 Hz indicate that this proton is trans-arranged with respect to vicinal proton H-4a. This proton gives rise to a multiplet at 4.62-4.69 ppm and at 4.20-4.28, in 4d and 6d, respectively. The occurrence and multiplicity of these signals clearly demonstrate the regiochemistry of the cycloaddition reaction. In contrast, in the 1H NMR spectra of regioisomer 5d (Figure 3,



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middle) the pyrrolidinyl protons H-3 and H-4a appear as singlet resonating at δ 4.63 and as doublet of doublets at 4.51 ppm (J = 8.1 Hz, J = 4.9 Hz), respectively.

4''

HN 2'' 3''

O O

δH-4a (J4a,5) δH-4 (J4,4a) δH-3 δH-4’’

4.62-4.69 4.05 (9.9) 7.49

4.51 (4.9, 8.2) 4.63 7.48

2 3 4' 2'

N

H

7 6 5

4a 4

H H Ar O

N Ph 6d

4.20-4.28 5.05 (9.6) 7.35

Figure 3. Selected 1H NMR data (δ in ppm, J in Hz) and NOE Correlations of Isomers 4d, 5d and 6d.

Comparison of the 1H NMR spectra of 4d and 6d reveals two significant differences concerning the chemical shifts of the signals of H-4 and H-4a. The H-4 resonance in 4d (4.05 ppm) is strongly upfield-shifted, with respect to the H-4 signal in 6d (5.05 ppm), a rather unusual spectral region for a pyrrolidinyl proton. In contrast, the resonance of H-4a (4.62-4.69 ppm) in 4d is shielded compared to that of 6d (4.20-4.28 ppm). These effects can be attributed to the relative orientation of the carbonyl oxindole group attached to C-2. Thus, the NOESY spectra of 6d (Figure S54 in SI) exhibits NOE contacts between H-4a and the aromatic proton H-4” revealing that C-2” and H-4a are in trans relationship. The absence of NOE contacts between the aromatic proton H-4” and H-4a in the NOESY spectra of 4d and 5d (Fig. S52 and S53, in ESI) indicates that C-2” and H-4a are in cis relationship. The regio- and the stereochemical outcome of the cycloaddition was furthermore ascertained by X-ray analysis of the crystal structure of cycloadducts 4e, 5d and 6d, whose ORTEP presentations are shown in Figures S55-S57 in the ESI. The occurrence of interesting intra- and inter-molecular


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hydrogen bonding in all three structures is discussed in detail in the ESI and represented there in Figures S59-S61.

Discussion of the Reaction Mechanism. On the basis of our experimental results and previous studies on the reaction mechanism,19 we propose in Scheme 3 a mechanistic pathway explaining the formation of 4 and 6 from the three-component reaction. The condensation of isatin 1a with the amino acid 2 should lead to the formation of the two possible intermediates I1 and I1’. After the decarboxylation process, two different types of ylides can be formed: W-shaped d1 and S-shaped d1’ (Scheme 2). Experiments suggest that 4 and 6 result from the cycloaddition of d1 to the dipolarophile 3. Hypothetically, the formation of product 6 could also involve the d1’ form (Scheme 2). However, this hypothesis was ruled out, since the formation of diastereoisomer 6 increased upon extending the reflux time of the reaction mixture and a total disappearance of the starting materials was finally observed (Table 1, entries 2 and 5).

Scheme 2. Formation of Ylides d1 and d1’, as well as their Possible Reaction with the Dipolarophile 3. O O+ N 1a H O

CO2H N H 2 O

O

N

N O

+

N I1' H O

-CO2

O

O N I1 H -CO2 Ar

Ar N Ph

HN O O

N

H N OAr Ph 6

3 H

O

N

O

O N d1' H

N Ph

N

HN

3 O

N d1 H


O

N

O O N Ph

H OAr 4

H


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Heating a solution of the major isomer 4 in methanol or acetonitrile for 4 hours causes exclusive interconversion to product 6. During this time, the competing formation of dipolarophile 1 is not observed (reaction monitored by TLC). Thus, we propose a ringopening retro-Mannich reaction for the observed epimerization (Scheme 3). This mechanism has been suggested to explain isomerization in spirooxindole alkaloids20 and pyrrolidine derivatives.21 Interesting, when extending the reaction time to 24h under reflux, regioisomer 5 is formed after formation of the imide 1 as monitored by TLC. Thereby, the proposed mechanism for the formation of regioisomer 5 involves a retro-1,3-dipolar cycloaddition reaction to generate a W-shaped d1’’ species, which then undergoes cycloreversion with the dipolarophile 3 through an exo-transition state (Scheme 3). This result was totally unexpected having no precedent in the literature. Neither an example concerning the isomerization at the carbon of the spirooxindole core of related 1,3-dipolar adducts, nor a retro-1,3-dipolar cycloaddition of spiropyrrolizidines was found. This tandem reaction is a straightforward route that allows access to a new isomeric class of spiropyrrolidizidines not accessible via direct 1,3-dipolar cycloaddition. All previously published studies showed that the cycloadducts were formed selectively through an exo-approach between the dipolarophile and the W-shaped ylide.


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Scheme 3. Proposed Mechanism Rationalizing the Formation of 5 and 6.

DFT calculations. To enlighten the experimental results, and unveiling the regio- and stereoselectivity of these [3+2] cycloaddition, we conducted a DFT computational study. We chose to focus on the reaction of the dipolarophile 3d with azomethine ylide d1. The stereochemistry of the cycloadducts is established by the ylide geometry and the endo/exo approach. Herein, we first explore the relative stability of the two possible isomers d1 and d1’ of the dipole-1,3 formed from the condensation of isatin 1a with L-proline 2 (Scheme 1). In agreement with related literature,18 the d1 form (W-shaped) is very slightly more stable than the d1’ form (S-shaped), by some 0.19 kcal.mol-1 (Scheme 4). Moreover, the attack of the dipolarophile on d1’ should result in an unfavourable inward movement of the proline ring towards the isatin ring leading to the steric hindrance between these two fragments, whilst in the case of d1 a favourable outward movement can occur (Scheme 4).22 Moreover, cycloadducts are always obtained from the W-shaped form and not from the S-shaped one.17, 18

Accordingly, calculations have been focused on the d1 conformation only.



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Scheme 4. Electronic Energies of Azomethine Ylides d1 (W-shaped) and d1’(S-shaped) Calculated at the B3LYP/6-31G (d,p) level. The Mode of the Attack of the Dipolarophile is also Represented. Inward movement

Outward movement N

N H

O

dipolarophile

dipolarophile

d1 : W -shaped

∆Ud1 – d1 = 0.0 kcal.mol-1

∆Ud1’ – d1 = 0.19 kcal.mol-1

A study using the frontier molecular orbital (FMO) model23 was first carried out. An analysis of the HOMO-LUMO energy values (Table S1, in ESI) indicates that the smaller energy difference is between HOMO (d1) and LUMO (3d) (∆E = 0.12 eV), which predicts that the HOMOdipole–LUMOdipolarophile interaction controls the cycloaddition reaction within a normal electron-demand reaction. The actual analysis of global and local properties is a powerful tool to understand the chemical reactivity of the system. Thus, electronic chemical potential µ, chemical hardness η and global electrophilicity ω were calculated. The electronic chemical potential µ describes the escaping tendency of electrons from an equilibrium system.24 Its negative value is the absolute molecular electronegativity, χ. The chemical hardness η revealsthe stability and reactivity of a chemical system.22-25 The global electrophilicity ω measures the propensity or capacity of a species to accept electrons.25g, 26 Only relevant data are discussed in the present text. All the data are however presented in Table S1 of the Supporting Information. The computed electronic chemical potential of the ylide d1 (µ = -3.320 eV) is higher than that of 3d (µ = -4.462 eV) and the chemical hardness of d1 (η = 2.204eV) is lower than of 3d (η = 2.231eV), suggesting that the net charge transfer will take place from d1 toward 3d. In addition, the electrophilicity of dipolarophile 3d (ω = 4.462eV) is greater than of d1 (ω =


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2.500eV), indicating that the 1,3-dipole will act as a nucleophile whereas 3d will act as an electrophile. The most favourable attack site can also be disclosed by theoretical calculations. The actual DFT-based local chemical reactivity Fukui function parameters for nucleophilic (fk+) and electrophilic (fk-) attacks, were calculated through the electrostatic potential (ESP) derived atomic populations using Eqn (1) and (2) respectively,27 f k+ = PkN +1 − PkN = q kN − q kN +1 (1) f k− = PkN − PkN −1 = q kN −1 − q kN (2)

with k, N, P and q, corresponding to the index of the atom, the number of electrons, the population number and the net charge stemming from calculations, respectively. The calculated local chemical reactivity parameters of d1 and 3d are shown in Figure S1 (in ESI). The most favorable two-center interaction takes place between C-5 (possessing the highest value of fk- = 0.215) of the dipole d1 and C-4 (possessing the highest value of fk+ = 0.106) of the dipolarophile 3d, leading primarily to the formation of the regioisomer 4d which is in agreement with experimental observations (Table 2). In order to explain the formation of regioisomer 5d in lower amount, the two regioisomeric pathways proposed in Scheme 5, have been studied. Four transitions states (TS), TS1-exo-4d, TS1-endo-4d, TS2-exo-5d and TS2endo-5d were found to be associated with the two regioisomeric channels endo/exo stereoisomeric approach modes between the azomethine ylide d1 and the dipolarophile 3d. Their cycloadducts were labeled 4d, 4’d, 5d and 5’d. The transition states are characterized by a saddle point with a single imaginary frequency. These TS are displayed in Figure 4. Kinetic and thermodynamic analyses can thus be carried out.



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Scheme 5. Plausible Mechanism for the Regio- and Stereoisomeric 1,3-Dipolar Cycloaddition Reaction of Dipolarophile 3 with Azomethine Ylide d1, Strike through Arrows Emphasize that the Product is not Experimentally Obtained


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2.767 2.795

SOI Hydrogen bond

2.009

2.053

TS1-exo

2.171

TS1-endo

Hydrogen bond

2.473

2.104

2.278

TS2-exo TS2-endo Figure 4. The Four Transition States for the 1,3-Dipolar Cycloaddition of d1 Across 3d, Optimized at the B3LYP/6-31G(d,p) Level. The Lengths of the Bonds Directly Involved in the Reaction are given in Å.

Differences in the Gibbs free energy (∆G), enthalpy (∆H) and entropy (∆S), for the different stationary points along the reactive pathways are reported in Table S2 in the SI. All the energy values have been corrected for the zero point energy. The kinetic parameters (activation energy, activation enthalpies and activation entropies between reactants and transition states) are first discussed. The energy requested to reach the TS, i.e. the activation energy, was shown to increase in the following order: TS1-exo< TS2-exo< TS1-endo< TS2-endo. The exo approach was found to be highly favored over the endo approach. The most favorable pathway, via the TS1-exo, exhibits a significantly lower activation energy (21.0 kcal.mol-1) than that stemming from the second most probable route via the TS2-exo (25.3 kcal.mol-1). The favored exo approaches compared with the endo attack fit experimental conclusions showing that mixtures of the two exo-regioisomeric are only observed.



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The close similarity between the four activation entropies, ranging in -48.1 to -51.8 cal mol-1 K-1, highlights that reactions are enthalpy-driven. From an energetic point of view, structural investigation (Figure 4) of these TS reveals that the dipole and dipolarophile are largely superimposed in the TS1-exo. Thus, the significantly lowest activation energy value of TS1-exo among the four TS can be partially explained by secondary orbital interactions (SOI)28 which occur between the oxygen atom of the carbonyl of isatin and the carbon atom of the carbonyl of the dipolarophile. Moreover, an additional hydrogen bond is formed in TS1-exo between one of the methylene hydrogen atoms of dipolarophile 3d with the carbonyl of the azomethine ylide d1 (2.430 Å). On the other hand, TS2-exo is only stabilized by a hydrogen bond, which occurs between one of the methylene hydrogen atoms of the proline ring of the azomethine ylide with carbonyl of dipolarophile 3d (2.453 Å).15b,

29

Thermodynamic analysis of the studied reactions can now be investigated. ∆G, ∆H and ∆S between reactants and products were also computed. The lowest ∆G values are achieved in the exo approach on 5d and 4d (0.5 and 1.2 kcal.mol-1, respectively). Similarly to the activation entropies, ∆S for these cycloadditions are found negative and their values were comparable, in the range of -51.6 to -54.8 cal K-1 mol-1. The exo approach unveils slightly more negative values than those corresponding to the endo one. Thus, the reactions are also enthalpy driven. Moreover, all cycloadditions are exothermic processes, and ∆H is in the range of -5.6 to -15.4 kcal.mol-1. It is worth noting that in the gas phase, calculations predict that these reactions have positive free Gibbs energies (∆G>0). Conversely, the experimental results in methanol showed that the reaction is spontaneous toward the products. The issue of these negative values for the free Gibbs enthalpy is the subject of forthcoming studies dealing with the presence of solvent. Nevertheless, these negative values suggest that this reaction is mainly kinetic dependent. Accordingly, thanks to DFT investigation, the most favorable pathway is established. It goes through TS1-exo (4d) and TS2-exo (5d) under kinetic control


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while 4d being slightly more stable than 5d. This conclusion is in perfect accordance with the experimental observation assigning the exo-regioisomer 4d as the major formed product whereas 5d is the minor one. All the transition states are concerted asynchronous as expected for a typical normal-demand 1,3-dipolar cycloaddition. To support this accordance, the two new bonds lengths are measured. At the TS associated with the regioisomeric channels 1 (Figure 4), the length of the C-2–C-3 forming bonds are 2.767 Å at TS1-endo and 2.795 Å at TS1-exo, while the distance between the C-4a and the C-4 atoms is 2.009 Å at TS1-endo and 2.053 Å at TS1-exo. At the TSs associated with the regioisomeric channels 2 (Figure 4), the length of the C-2–C-3 forming bonds are 2.473 Å at TS2-endo and 2.278 Å at TS2-exo, while the distance between the C-4a and the C-4 atoms is 2.104 Å at TS2-endo and 2.171 Å at TS2-exo. The extent of the asynchronicity of the bond-formation can thus be measured by the difference between the lengths of the two σ bonds being formed in the reaction, i.e., ∆d = l1-l2. The asynchronicity at the regioisomeric channel 1 is ∆d = 0.75 Å at TS1-endo and 0.74 Å at TS1-exo, while that at the regioisomeric channel 2 is ∆d = 0.37 Å at TS2-endo and 0.10 Å at TS2-exo. Therefore the formation of the TS associated with channel 1 is favored. Accordingly, DFT investigation is in perfect agreement with the experimental observation assigning the exo-regioisomer 4d as the major formed product.

Synthesis of the Spiropyrrolizidines 7 and Piperazine 8. Encouraged by these results, we examined the regio- and stereoselectivity of the three-component 1,3-dipolar cycloaddition reaction of the dipolarophile 3, L-proline with other cyclic diketones such as indenoquinoxaline-11-one 1b and acenaphthenequinone 1c (Scheme 6). When the reaction was investigated with 1b in MeOH as reaction medium, the spiropyrrozolidines 7a-c were obtained in good yields as sole stereoisomers (Table 3, entries 1-3). Surprisingly, the use of 1c



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Page 18 of 39

as reaction component in the cycloaddition led, along with the formation the spiropyrrolizidine derivatives 7d-h, to creation of the fused piperazine 8, a dimer of the 1,3dipole (Table 3, entries 4-8).

Scheme 6. Reaction of (E)-3-arylidene-1-phenyl-pyrrolidine-2,5-diones 3, L-proline with Cyclic Ketones 1b and 1c.

Table 3. Synthesis of Dispiropyrrolizidine Derivatives 7 and Piperazine 8 Entry 1 2 2 4 5 6 7 8

diketone 1b 1b 1b 1c 1c 1c 1c 1c

Ar p-MeC6H4 p-MeOC6H4 p-ClC6H4 C 6 H5 p-MeC6H4 p-MeOC6H4 p-ClC6H4 p-BrC6H4

Products 7a 7b 7c 7d + 8 7e + 8 7f + 8 7g + 8 7h + 8

Ratioa 7/8 100 : 00 100 : 00 100 : 00 70 : 30 67 : 33 62 : 38 75 : 25 80 : 20

a

Isolated yield after purification by column chromatography. bRelative ratios were determined by 1H NMR from the crude reaction with 1c.

Synthesis and Characterization of Fused Piperazines 8. To the best of our knowledge, the lock and key chemistry of the dimerization of an azomethine ylide derived from acenaphthenequinone 1c and L-proline 2 was not yet documented in the literature. However some articles reported the synthesis of the [3+3] cycloaddition (dimerization) of the


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azomethine ylide stemming from condensation of isatin 1a and L-proline 2.30 We were thus interested in the dimerization reaction of d2 as tool for building novel dispiroacenaphthenones. These reagents, admixed together without any dipolarophile, afforded two compounds after 2 hours in refluxing methanol (Scheme 8). After separation by column chromatography, they were identified as dimer 8 and its regioisomer 9 in a 70:30 ratio. Structural elucidation of these compounds 8 and 9 was accomplished using the NMR spectroscopic data and a single-crystal X-ray diffraction study. In the 1H NMR spectra, six aromatic protons were found, followed by seven protons in the aliphatic region, indicating that these molecules are symmetric. In the hypothetical case of formation of the alternative isomers 8’ and 9’ (Scheme 7), the observation of the twice number of protons in the aliphatic and aromatic regions would be expected. Since 8 and 9 are difficult to distinguish by NMR spectroscopy, we therefore characterized piperazine 8 by means of a single-crystal X-ray diffraction study, whose his ORTEP is shown in Figures S58 in the ESI.

To explain the reaction mechanism, it should be noted that the dipole presents two mesomeric forms d2 and d2’. Thus, two pathways are possible: the first one occurring in a head-head fashion of d2 + d2’ leading to the formation of compounds 8 and 8’; the second consisting of the cycloaddition by a head-tail way of d2 + d2 giving the dispiro-acenaphthenones 9 and 9’. The observed regioselectivity can be explained based on the transition states depicted in Scheme 8. In fact, the possible path 2 led to repulsive electronic interaction between the two acenaphthenone cores of d2 and d2’ in TS-8’. Furthermore, TS-9’ presents electrostatic repulsion between the pyrrolidine residue and the acenaphthenone moiety of d2 (path 3). For these reasons, formation of dimers 8’ and 9’ is unfavourable. However, the TS-8 leading to product 8 (path 1) is the more favourable and predominant due to a secondary orbital interaction (SOI) between the orbital of the carbonyl group of d2 with those of the ylide d2’ (ratio of 8:9 is 70:30).



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Page 20 of 39

Scheme 7. Proposed Dimerization Mechanism of Azomethine Ylides d2 and d2’ O O

+

N H

1d

CO2H 2 N

T ail

N Path 2

O

O

N

Path 1

O

O

N

Head

d2

d2

Tr ansoid or ientation of azomethine ylide

d2' d2 Cisoid or ientation of azomethine ylide N

N

O

N

N O

O

N

O

O Path 2

Path 4

Path 1

Path 3

O N

O

O

O

O

N

O O

N O SOI

TS-9'

Destabilized by repulsion steric interaction

TS-9

O

N

N

N

N N

TS-8

TS-8'

Destabilized by repulsion electronic interaction

O 5

3

2

5

6

N

N N 9

O

7 8

N

9

OO 8' Not f or med

9 8 7

N 3

9'

6

N

N

O Minor

N

2

OO 8 Major

Not Formed

CONCLUSION We reported the synthesis of a very new series of spiropyrrolizidine derivatives via a threecomponent 1,3-dipolar cycloaddition reaction of (E)-3-arylidene-1-phenyl-pyrrolidine-2,5diones,

L-proline

and

cyclic

ketones

isatin,

indenoquinoxaline-11-one

and

acenaphthenequinone. We showed that spirooxindolepyrrolizidine undergoes a reversible ring opening cyclization reaction affording a new family of compounds with unusual relative stereochemistry. Furthermore, these cycloadducts undergo retro-1,3-dipolar cycloaddition yielding an unexpected regioisomers. An analysis based on theoretical calculations using the DFT approach at the B3LYP/6-31G(d,p) level revealed that the spirocycloadduct 4 is obtained through a 1,3-dipolar cycloaddition reaction via a high asynchronous mechanism, with a very


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low activation energy as compared to the other possible reaction paths. This outcome is in agreement with the experimental observations. Another important highlight of the present work is the isolation of polycyclic fused piperazines, stemming from reaction of the dipolarophiles with azomethine ylides derived from condensation of acenaphthenequinone and L-proline. This methodology implying a stepwise [3+3] cycloaddition pathway was further developed allowing to access new dispiropiperazine-containing compounds. These compounds were fully characterized for the first time in literature. The biological activities of our spiropyrrolizidine derivatives will be investigated. We intend also to perform calculations on the [3+3] cycloaddition using the DFT approach.

EXPERIMENTAL SECTION General experimental methods NMR spectra were recorded on a 300 MHz spectrometer operating at 75 MHz for the

13

C

NMR spectra. Chemical shifts are reported in ppm with the solvent resonance as the internal standard (CDCl3: δ 7.26 ppm in 1H NMR and δ 75.00 ppm in

13

C NMR). The following

abbreviations were used to explain the multiplicities: bs = broad singlet, s = singlet, d = doublet, dd = doublet of doublets, m = multiplet. IR spectra were recorded in the ATR mode. Elemental analyses were performed on a CHNS-elemental analyzer. Materials: thin-layer chromatography (TLC): TLC plates (Merck, silica gel 60 F254 0.2 mm 200×200 nm); substances were detected using UV light at 254 nm. The (E)-3-arylidene-1-phenylpyrrolidine-2,5-diones 3a-e were prepared by Wittig reaction between N-phenyl maleimide and aromatic aldehyde.30

General procedure for the preparation of cycloadducts 4-6 A mixture of 3 (0.5 mmol), L-proline 2 (0.75 mmol) and isatin 1a or acenaphthenequinone 1b was refluxed in methanol (10 mL) for 24h. After completion



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of the reaction as monitored from TLC, the solvent was removed under reduced pressure and residue was chromatographed on silica gel employing ethylacetatecyclohexane (3:7 v/v) as eluent to obtain the pure products 4-6. Spiro[2,3”]oxindole-spiro-[3,3’]-N-phenylsuccinimide-4-phenylhexahydro-1Hpyrrolizine 4a White solid (144 mg, 82%); mp 177-178 °C; 1H NMR δ (ppm): 8.93 (bs, 1H), 6.817.57 (m, 14H), 4.73-4.78 (m, 1H), 4.16 (d, J = 9.9 Hz, 1H), 3.30-3.42 (m and d, , J = 18.9 Hz, 2H), 2.79-2.85 (m, 1H), 2.71 (d, J = 18.9 Hz, 1H), 1.97-2.19 (m, 3H), 1.421.81 (m, 1H);

13

C NMR δ 178.1, 177.2, 173.2, 140.8, 135.7, 131.1, 129.5, 129.1,

128.6, 128.4, 128.0, 127.9, 127.4, 125.9, 124.6, 121.8, 110.1, 76.9, 67.8, 64.8, 56.7, 47.0, 35.2, 29.5, 26.4; IR ν 3225, 1778, 1707 cm-1; Anal. Calcd. For C29H25N3O3: C, 75.14; H, 5.44; N, 9.07; found: C, 75.18; H, 5.45; N, 8.98. Spiro[2,3”]oxindole-spiro-[3,3’]-N-phenylsuccinimide-4-(4-methylphenyl)hexahydro-1Hpyrrolizine 4b White solid (139 mg, 90%); mp 240-241 °C; 1H NMR δ (ppm): 8.96 (bs, 1H), 6.86-7.60 (m, 13H), 4.73-4.77 (m, 1H), 4.15 (d, J = 10.2 Hz, 1H), 3.42 (d, J = 18.7 Hz, 1H), 3.33-3.35 (m, 1H), 2.80-2.85 (m, 1H), 2.75 (d, J = 18.7 Hz, 1H), 2.38 (s, 3H), 2,02-2.20 (m, 3H), 1.81-2.20 (m, 1H);

13

C NMR δ 178.1, 177.2, 173.3, 140.8, 137.1, 132.5, 131.2, 129.4, 128.9, 128.3,

128.0, 127.9, 125.9, 124.7, 121.8, 110.1, 76.8, 67.7, 64.8, 56.4, 46.9, 35.1, 29.5, 26.4, 20.4; IR ν 3247, 1787, 1708 cm-1; Anal. Calcd. For C30H27N3O3: C, 75.45; H, 5.70; N, 8.80; found: C, 75.41; H, 5.67; N, 8.75. Spiro[2,3”]oxindole-spiro-[3,3’]-N-phenylsuccinimide-4-(4-methoxyphenyl)hexahydro1H-pyrrolizine 4c White solid (160 mg, 92%); mp 232-233 °C; 1H NMR δ (ppm): 8.92 (bs, 1H), 6.847.58 (m, 13H), 4.80 (m, 1H), 4.11 (d, J = 9.9 Hz, 1H), 3.83 (s, 3H), 3.33-3.43 (d and


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m, J = 18.7 Hz, 2H), 2.83 (m, 1H), 2.75 (d, J = 18.7 Hz, 1H), 1,99-2.20 (m, 3H), 1.781.82 (m, 1H);

13

C NMR δ 177.7, 173.9, 159.3, 141.2, 130.6, 130.1, 128.9, 128.5,

128.5, 126.4, 122.4, 114.7, 114.5, 110.7, 76.6, 68.4, 65.1, 56.6, 55.2, 47.6, 35.6, 30.0, 26.9; IR ν 3222, 1787, 1708 cm-1; Anal. Calcd. For C30H27N3O4: C, 73.01; H, 5.51; N, 8.51; found: C, 73.09; H, 5.45; N, 8.46. Spiro[2,3”]oxindole-spiro-[3,3’]-N-phenylsuccinimide-4-(4-chlorophenyl)hexahydro-1Hpyrrolizines 4d White solid (111 mg, 85%); mp 213-214 °C; 1H NMR δ (ppm): 8.41 (bs, 1H), 6.767.50 (m, 13H), 4.62-4.69 (m, 1H), 4.05 (d, J = 9.9 Hz, 1H), 3.32-3.41 (m, 1H), 3.23 (d, J = 18.7 Hz, 1H), 2.75-2.81 (m, 1H), 2.60 (d, J = 18.7 Hz, 1H), 1.89-2.18 (m, 3H), 1.70-1.79 (m, 1H);

13

C NMR δ 178.1, 178.0, 173.7, 141.1, 134.9, 133.9, 131.4, 131.1,

130.2, 129.5, 129.3, 129.1, 129.0, 128.6, 128.4, 126.4, 122.6, 110.5, 76.6, 68.9, 65.1, 57.0, 47.6, 36.1, 29.9, 26.3; IR ν 3266, 1771, 1706 cm-1; Anal. Calcd. For C29H24ClN3O3: C, 69.95; H, 4.86; N, 8.44; found: C, 70.00; H, 4.94; N, 8.50. Spiro[2,3”]oxindole-spiro-[3,3’]-N-phenylsuccinimide-4-(4-fluorophenyl)hexahydro-1Hpyrrolizine 4e White solid (120 mg, 91%); mp 216-217 °C; 1H NMR δ (ppm): 8.45 (bs, 1H), 6.837.56 (m, 13H), 4.67-4.74 (m, 1H), 4.12 (d, J = 10.2 Hz, 1H), 3.36-3.44 (m, 1H), 3.29 (d, J = 18.6 Hz, 1H), 2.79-2.85 (m, 1H), 2.41 (d, J = 18.6 Hz, 1H), 1.96-2.19 (m, 3H), 1.73-1.84 (m, 1H); 13C NMR δ 177.7, 177.5, 173.0, 160.3, 140.7, 131.7, 131.6, 131.1, 130.8, 130.7, 129.6, 128.3, 128.0, 125.8, 124.5, 121.9, 115.6, 115.3, 109.9, 76.4, 68.4, 64.7, 56.4, 47.0, 35.5, 29.3, 25.8; IR ν 3198, 1777, 1702 cm-1; Anal. Calcd. For C29H24FN3O3: C, 72.34; H, 5.02; N, 8.73; found: C, 72.26; H, 5.08; N, 8.77.



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Page 24 of 39

Spiro[2,3”]oxindole-spiro-[4,3’]-N-phenylsuccinimide-3-phenylhexahydro-1Hpyrrolizines 5a White solid (25 mg, 82%); mp170-171 °C; 1H NMR δ (ppm): 7.81 (bs, 1H), 6.74-7.71 (m, 14H), 5.29 (s, 1H), 4.60 (dd, J = 8.1 Hz, J = 5.1 Hz, 1H), 3.21-3.34 (d and m, J = 18.9 Hz, 2H), 3.13 (d, J = 18.9 Hz, 1H), 2.74-2.78 (m, 1H), 1.87-2.22 (m, 4H);

13

C

NMR δ 179.9, 178.2, 174.4, 140.9, 133.0, 131.6, 131.5, 129.1, 129.0, 128.5, 128.4, 127.9, 127.8, 127.3, 126.1, 125.9, 125.1, 121.9, 109.3, 74.9, 73.8, 58.3, 56.4, 48.7, 41.2, 27.0, 25.0, IR ν 3228, 1780, 1707 cm-1; Anal. Calcd. For C29H25N3O3: C, 75.14; H, 5.44; N, 9.07; found: C, 75.25; H, 5.36; N, 9.16. Spiro[2,3”]oxindole-spiro-[4,3’]-N-phenylsuccinimide-3-(4-methylphenyl)hexahydro-1Hpyrrolizines 5b White solid (38 mg, 90%); mp 235-236 °C; 1H NMR δ (ppm): 7.60 (bs, 1H), 6.75-7.49 (m, 13H), 4.74 (s, 1H), 4.60 (dd, J = 7.8 Hz, J = 4.8 Hz, 1H), 3.21-3.35 (d and m, J = 18.6 Hz, 2H), 3.15 (d, J = 18.6 Hz, 1H), 2.75-2.80 (m, 1H), 1.85-2.24 (m and s, 7H); 13

C NMR δ 180.4, 178.6, 175.0, 141.4, 137.5, 130.3, 129.6, 129.4, 129.0, 128.4,

126.4,125.6, 122.4, 109.7, 77.1, 75.3, 74.3, 58.8, 56.6, 49.2, 41.7, 27.5, 25.4,20.8; IR ν 3249, 1787, 1710 cm-1; Anal. Calcd. For C30H27N3O3: C, 75.45; H, 5.70; N, 8.80; found: C, 75.37; H, 5.79; N, 8.91. Spiro[2,3”]oxindole-spiro-[4,3’]-N-phenylsuccinimide-3-(4-methoxyphenyl)hexahydro1H-pyrrolizines 5c White solid (40 mg, 92%); mp 223-224 °C; 1H NMR δ (ppm): 7.84 (bs, 1H), 6.65-7.48 (m, 13H), 4.69 (s, 1H), 4.58 (dd, J = 8.1 Hz, J = 4.8 Hz, 1H), 3.67 (s 3H), 3.21-3.30 (m and d, J = 18.9 Hz, 2H), 3.15 (d, J = 18.9 Hz, 1H), 2.76-2.78 (m, 1H),1.88-2.18 (m, 4H);

13

C NMR δ 180.5, 179.1, 175.2, 159.1, 141.3, 130.7, 129.6, 129.1, 128.5, 126.6,

126.4, 125.6, 122.5, 114.3, 109.9, 77.2, 75.2, 74.5, 58.8, 55.0, 49.4, 41.7, 27.5, 25.5;


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IR ν 3221, 1789, 1709 cm-1; Anal. Calcd. For C30H27N3O4: C, 73.01; H, 5.51; N, 8.51; found: C, 73.07; H, 5.58; N, 8.47. Spiro[2,3”]oxindole-spiro-[4,3’]-N-phenylsuccinimide-3-(4-chlorophenyl)hexahydro-1Hpyrrolizine 5d White solid (59 mg, 85%); mp 189-190 °C; 1H NMR δ (ppm): 7.86 (bs, 1H), 6.69-7.42 (m, 13H), 4.63 (s, 1H), 4.51 (dd, J = 8.1 Hz, J = 4.8 Hz, 1H), 3.17-3.24 (d and m, J = 18.7, 2H), 3.00 (d, J = 18.7 Hz, 1H), 2.66-2.71 (m, 1H), 2.09-2.16 (m, 1H), 1.75-1.97 (m, 3H);

13

C NMR δ 180.2, 178.7, 174.8, 141.3, 134.0, 131.9, 131.9, 131.0, 129.9,

129.2, 129.1, 128.6, 126.4, 126.2, 125.6, 122.6, 110.1, 75.5, 74.5, 58.8, 55.9, 49.4, 41.7, 27.6, 25.5; IR ν 3264, 1770, 1706 cm-1; Anal. Calcd. For C29H24ClN3O3: C, 69.95; H, 4.86; N, 8.44; found: C, 70.01; H, 4.97; N, 8.55. Spiro[2,3”]oxindole-spiro-[4,3’]-N-phenylsuccinimide-3-(4-fluorophenyl)hexahydro-1Hpyrrolizine 5e White solid (65 mg, 91%); mp 197-198 °C; 1H NMR δ (ppm): 7.86 (bs, 1H), 6.69-7.42 (m, 13H), 4.63 (s, 1H), 4.51 (dd, J = 8.1 Hz, J = 4.8 Hz, 1H), 3.17-3.24 (d and m, J = 18.7 Hz, 2H), 3.00 (d, J = 18.7 Hz, 1H), 2.66-2.71 (m, 1H), 2.09-2.16 (m, 1H), 1.751.97 (m, 3H);

13

C NMR δ 180.0, 178.4, 174.9, 141.6, 131.4, 131.3, 129.1, 128.5,

126.3, 125.6, 122.5, 116.0, 115.8, 110.2, 75.6, 74.3, 58.6, 55.9, 49.4, 41.5, 27.7, 25.6; IR ν 3205, 1778, 1704 cm-1; Anal. Calcd. For C29H24FN3O3: C, 72.34; H, 5.02; N, 8.73; found: C, 72.40; H, 4.99; N, 8.79. Spiro[2,3”]oxindole-spiro-[3,3’]-N-phenylsuccinimide-4-phenylhexahydro-1Hpyrrolizine 6a White solid (21 mg, 82%); mp 190-191 °C; 1H NMR δ (ppm): 7.72 (bs, 1H), 6.64-7.49 (m, 14H), 5.06 (d, J = 9.6 Hz, 1H), 4.29-4.32 (m, 1H), 3.38 (d, J = 18.1 Hz, 1H), 2.87 (d, J = 18.1 Hz, 1H), 2.72-2.74 (m, 2H), 2.05-2.26 (m, 4H);


13

C NMR δ 178.4, 175.8,


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Page 26 of 39

173.5, 141.3, 135.9, 131.2, 130.1, 129.1, 129.0, 128.9, 128.8, 128.8, 128.6, 128.5, 127.8, 126.3, 126.1, 122.5, 110.0, 77.4, 66.3, 66.0, 49.6, 47.4, 34.2, 30.0; IR ν 3279, 1772, 1725, cm-1; Anal. Calcd. For C29H25N3O3: C, 75.14; H, 5.44; N, 9.07; found: C, 75.23; H, 5.52; N, 9.01. Spiro[2,3”]oxindole-spiro-[3,3’]-N-phenylsuccinimide-4-(4-methylphenyl)hexahydro-1Hpyrrolizine 6b White solid (37 mg, 90%); mp 164-165 °C; 1H NMR δ (ppm): 6.68-7.50 (m, 14H), 5.03 (d, J = 9.9 Hz, 1H), 4.27 (m, 1H), 3.37 (d, J = 18.1 Hz, 1H), 2.89 (d, J = 18.1 Hz, 1H), 2.76 (m, 2H), 2.33 (s, 3H), 2.05-2.28 (m, 4H);

13

C NMR δ 178.3, 174.8, 173.5,

141.2, 137.5, 132.7, 131.3, 130.0, 129.6, 128.9, 128.5, 126.3, 122.4, 109.8, 77.9, 66.3, 66.0, 58.4, 49.3, 47.4, 34.2, 30.0, 21.0; IR ν 3251, 1786, 1720 cm-1; Anal. Calcd. For C30H27N3O3: C, 75.45; H, 5.70; N, 8.80; found: C, 75.52; H, 5.61; N, 8.87. Spiro[2,3”]oxindole-spiro-[3,3’]-N-phenylsuccinimide-4-(4-methoxyphenyl)hexahydro1H-pyrrolizines 6c White solid (26 mg, 92%); mp 182-183 °C; 1H NMR δ (ppm): 6.71-7.54 (m, 14H), 5.01 (d, J = 9.6 Hz, 1H), 4.26-4.29 (m, 1H), 3.82 (s, 3H), 3.38 (d, J = 18 Hz, 1H), 2.91 (d, J = 18 Hz, 1H), 2.76-2.78 (m, 2H), 2.30 (m, 1H), 2.07 (m, 3H);

13

C NMR δ 180.0,

175.2, 174.5, 159.5, 140.3, 132.1, 129.7, 129.4, 129.1, 128.7, 128.3, 126.2, 122.4, 114.4, 77.9, 66.1, 58.3, 55.2, 49.2, 34.1, 30.7, 29.8; IR ν 3230, 1787, 1723 cm-1; Anal. Calcd. For C30H27N3O4: C, 73.01; H, 5.51; N, 8.51; found: C, 72.94; H, 5.42; N, 8.61. Spiro[2,3”]oxindole-spiro-[3,3’]-N-phenylsuccinimide-4-(4-chlorophenyl)hexahydro-1Hpyrrolizine 6d White solid (41 mg, 85%); mp 228-229 °C; 1H NMR δ (ppm): 7.65 (bs, 1H), 6.63-7.50 (m, 13H), 5.05 (d, J = 9.6 Hz, 1H), 4.20-4.28 (m, 1H), 3.39 (d, J = 18.1 Hz, 1H), 2.702.83 (m and d, J = 18.1 Hz, 3H), 2.25-2.27 (m, 1H), 2.00-2.16 (m, 3H);


13

C NMR δ

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178.1, 174.7, 173.1, 143.9, 134.5, 133.7, 131.2, 130.1, 130.0, 129.1, 128.9, 128.6, 126.2, 126.0, 122.5, 110.0, 78.0, 66.3, 65.9, 48.7, 47.4, 34.1, 30.7, 30.0; IR ν 3264, 1772, 1715 cm-1; Anal. Calcd. For C29H24ClN3O3: C, 69.95; H, 4.86; N, 8.44; found: C, 70.03; H, 4.95; N, 8.33. Spiro[2,3”]oxindole-spiro-[3,3’]-N-phenylsuccinimide-4-(4-fluorophenyl)hexahydro-1Hpyrrolizine 6e White solid (33 mg, 91%); mp 230-231 °C; 1H NMR δ (ppm): 7.71 (bs, 1H), 6.66-7.50 (m, 13H), 5.07 (d, J = 9.6 Hz, 1H), 4.21-4.27 (m, 1H), 3.40 (d, J = 18 Hz, 1H), 2.712.86 (m and d, J = 18 Hz, 3H), 2.24-2.28 (m, 1H), 2.01-2.12 (m, 3H);

13

C NMR δ

178.3, 174.7, 173.0, 160.6, 141.3, 131.7, 131.3, 130.3, 130.2, 130.1, 128.9, 128.5, 126.4, 126.2, 122.5, 116.0, 115.7, 109.9, 78.0, 66.5, 65.9, 48.9, 47.4, 34.1, 30.7, 29.9; IR ν 3200, 1779, 1715 cm-1; Anal. Calcd. For C29H24FN3O3: C, 72.34; H, 5.02; N, 8.73; found: C, 72.42; H, 4.95; N, 8.78. General procedure for the preparation of spiro-indenoquinoxaline pyrrolizidines 7a-c A mixture of ninhydrin (0.5 mmol) and 1,2-phenylenediamine (0.5 mmol) and L-proline 2 (0.5 mmol) was stirred for 10 min in 10 mL of methanol followed by the addition of dipolarophile 3 (0.5 mmol). The mixture was then refluxed for 4h until completion of the reaction as evidenced by TLC. The solvent was removed under reduced pressure and the crude product obtained was purified by column chromatography on silica gel using ethylacetate-cyclohexane (3:7 v/v) as eluent to provide the pure product 7a-c. Spiro[2,11’’]indeno-[1,2b]-quinoxaline-spiro-[3,3’]-N-phenylsuccinimide-4-(4methylphenyl)hexahydro-1H-pyrrolizines 7a Yellow solid (197 mg, 70%); mp 209-210 °C; 1H NMR δ (ppm): 6.52-8.27 (m, 17H), 4.794.87 (m, 1H), 4.51 (d, J = 10.2 Hz, 1H), 4.14 (d, J = 18.3 Hz, 1H), 2.87-2.96 (m, 1H), 2.72 (d, J = 18.1 Hz, 1H), 2.61-2.68 (m, 1H), 2.32 (s, 3H), 2.12-2.29 (m, 3H), 1.66-1.92 (m, 1H); 13C



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NMR δ 175.4, 172.8, 160.7, 152.8, 144.4, 142.4, 140.7, 137.1, 137.1, 132.4, 131.0, 130.3, 129.7, 129.6, 129.5, 129.5, 129.2, 128.7, 128.5, 128.5, 128.2, 128.0, 127.6, 125.9, 125.5, 122.1, 78.0, 67.1, 66.5, 53.7, 46.1, 34.7, 30.4, 28.1, 20.4; IR ν 1784, 1574 cm-1; Anal. Calcd. For C37H30N4O2: C, 78.98; H, 5.37; N, 9.96; found: C, 79.09; H, 5.32; N, 10.01. Spiro[2,11’’]indeno-[1,2b]-quinoxaline-spiro-[3,3’]-N-phenylsuccinimide-4-(4methoxyphenyl)hexahydro-1H-pyrrolizidine 7b Yellow solid (251 mg, 87%); mp 184-185 °C; 1H NMR δ (ppm): 6.56-8.32 (m, 17H), 4.84 (m, 1H), 4.53 (d, J = 10.2 Hz, 1H), 4.20 (d, J = 18.3 Hz, 1H), 3.83 (s, 3H), 2.95-2.97 (m, 1H), 2.70-2.80 (d and m, J = 18.3 Hz, 2H), 2.18-2.30 (m, 3H), 1.90-1.94 (m, 1H);

13

C NMR δ

176.2, 173.3, 159.3, 153.3, 142.9, 141.2, 131.4, 130.8, 130.2, 130.0, 129.3, 128.9, 128.7, 128.2, 127.7, 126.0, 122.6, 114.5, 78.4, 67.7, 67.0, 55.2, 53.8, 46.7, 35.2, 30.8, 28.5; IR ν 1784, 1577 cm-1; Anal. Calcd. For C37H30N4O3: C, 76.80; H, 5.23; N, 9.68; found: C, 76.68; H, 5.29; N, 9.72. Spiro[2,11’’]indeno-[1,2b]-quinoxaline-spiro-[3,3’]-N-phenylsuccinimide-4-(4chlorophenyl)hexahydro-1H-pyrrolizines 7c Yellow solid (247 mg, 85%); mp 206-207 °C; 1H NMR δ (ppm): 6.51-8.25 (m, 17H), 4.76-4.84 (m, 1H), 4.74 (d, J = 10.2 Hz, 1H), 4.03 (d, J = 18.1 Hz, 1H), 2.90-2.98 (m, 1H), 2.57-2.67 (d and m, J = 18.1 Hz, 2H), 2.10-2.25 (m, 3H), 1.82-1.87 (m, 1H);

13

C

NMR δ 172.9, 161.0, 153.2, 144.5, 142.9, 141.2, 137.6, 134.7, 133.9, 133.2, 131.3, 131.2, 130.8, 130.5, 130.2, 130.2, 129.9, 129.4, 129.3, 129.2, 129.0, 128.9, 128.8, 128.5, 128.3, 128.2, 126.6, 126.3, 125.9, 122.6, 78.4, 76.9, 76.5, 67.9, 66.9, 53.9, 46.6, 35.4, 30.7, 28.3; IR ν1782, 1576 cm-1; Anal. Calcd. For C36H27ClN4O2: C, 74.16; H, 4.67; N, 9.61; found: C, 74.06; H, 4.61; N, 9.69.


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General procedure for the preparation of cycloadducts 7d-h and piperazine 8 A mixture of 3 (0.5 mmol), L-proline 2 (0.75 mmol) and acenaphthenequinone 1b was refluxed in methanol (10 mL) for 2h. After completion of the reaction as monitored from TLC, the solvent was removed under reduced pressure and residue was chromatographed on silica gel employing ethylacetate-cyclohexane (3:7 v/v) as eluent to obtain the pure products 7d-h and piperazine 8. Spiro[2,2”]acenaphthene-1”-one-spiro-[3,3’]-N-phenylsuccinimide-4-phenylhexahydro1H-pyrrolizine 7d Yellow solid (204 mg, 70%); mp 202-203 °C; 1H NMR δ (ppm): 6.48-8.10 (m, 16H), 4.66 (m, 1H), 4.19 (d, J = 9.9 Hz, 1H), 3.30-3.33 (m, 1H), 3.15 (d, J = 18.4 Hz, 1H), 2.63-2.96 (m and d, J = 18.4 Hz, 2H), 1.95-2.14 (m, 2H), 1.79 (m, 1H);

13

C NMR δ

202.5, 177.4, 173.0, 141.7, 135.7, 134.2, 131.8, 130.9, 130.5, 130.4, 129.0, 128.6, 128.4, 127.9, 127.7, 127.5, 125.7, 125.5, 124.5, 121.8, 80.5, 67.9, 64.8, 57.5, 47.5, 34.8, 30.0, 26.6; IR ν 1787, 1715 cm-1; Anal. Calcd. For C33H26N2O3: C, 79.50; H, 5.26; N, 5.62; found: C, 79.41; H, 5.33; N, 5.70. Spiro[2,2”]acenaphthene-1”-one-spiro-[3,3’]-N-phenylsuccinimide-4-(4methylphenyl)hexahydro-1H-pyrrolizines 7e Yellow solid (171 mg, 67%); mp 208-209 °C; 1H NMR δ (ppm): 6.54-8.61 (m, 15H), 4.68 (m, 1H), 4.21 (d, J = 10.2 Hz, 1H), 3.34-3.37 (m, 1H), 3.19 (d, J = 18.6 Hz, 1H), 2.69-2.75 (m and d, J = 18.6 Hz, 2H), 2.34 (s, 3H), 2.02-2.19 (m, 3H), 1.83-1.88 (m, 1H);

13

C NMR δ 205.1, 177.9, 173.6, 142.1, 137.7, 132.9, 132.3, 131.5, 131.0, 130.9,

129.8, 129.3, 129.1, 128.8, 128.4, 128.2, 126.2, 125.9, 125.1, 122.3, 80.9, 68.3, 65.3, 57.7, 48.0, 35.3, 30.4, 27.1, 21.0; IR ν 1777, 1708 cm-1; Anal. Calcd. For C34H28N2O3: C, 79.67; H, 5.51; N, 5.46; found: C, 79.68; H, 5.44; N, 5.41.



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Spiro[2,2”]acenaphthene-1”-one-spiro-[3,3’]-N-phenylsuccinimide-4-(4methoxyphenyl)hexahydro-1H-pyrrolizines 7f Yellow solid (190 mg, 75%); mp 212-212 °C; 1H NMR δ (ppm): 6.45-8.10 (m, 15H), 4.58-4.61 (m, 1H), 4.13 (d, J = 9.9 Hz, 1H), 3.74 (s, 3H), 3.28-3.30 (m, 1H), 3.13 (d, J = 18.7 Hz, 1H), 2.63-2.69 (m and d, J = 18.7 Hz, 2H), 1.97-2.35 (m, 3H), 1.82-1.90 (m, 1H);

13

C NMR δ 202.8, 177.5, 173.1, 158.7, 131.8, 130.9, 130.5, 130.4, 130.0,

128.3, 127.9, 127.7, 127.4, 125.7, 125.4, 124.6, 121.8, 114.0, 80.4, 67.9, 64.8, 56.9, 54.7, 47.5, 34.7, 30.0, 26.6; IR ν 1776, 1710 cm-1; Anal. Calcd. For C34H28N2O4: C, 77.25; H, 5.34; N, 5.30; found: C, 77.30; H, 5.28; N, 5.38. Spiro[2,2”]acenaphthene-1”-one-spiro-[3,3’]-N-phenylsuccinimide-4-(4chlorophenyl)hexahydro-1H-pyrrolizines 7g Yellow solid (200 mg, 90%); mp 220-221 °C; 1H NMR δ (ppm): 6.65-8.21 (m, 15H), 4.66-4.73 (m, 1H), 4.22 (d, J = 9.9 Hz, 1H), 3.41-3.50 (m, 1H), 3.15 (d, J = 18.9 Hz, 1H), 2.73-2.78 (m, 1H), 2.63 (d, J = 18.9 Hz, 1H), 2.19-2.25 (m, 2H), 1.99-2.11 (m, 1H), 1.82-1.98 (m, 1H);

13

C NMR δ 202.7, 178.2, 173.3, 142.3, 134.9, 134.4, 133.9,

132.4, 131.3, 130.9, 130.9, 129.5, 129.3, 129.1, 128.9, 128.5, 128.3, 128.2, 126.4, 126.1, 125.0, 122.5, 80.9, 68.8, 65.1, 57.8, 48.1, 35.5, 30.4, 26.8; IR ν 1778, 1715 cm1

; Anal. Calcd. For C33H25ClN2O3: C, 74.36; H, 4.73; N, 5.26; found: C, 74.46; H,

4.81; N, 5.34. Spiro[2,2”]acenaphthene-1”-one-spiro-[3,3’]-N-phenylsuccinimide-4-(4bromophenyl)hexahydro-1H-pyrrolizines 7h Yellow solid (225 mg, 78%); mp 216-217 °C;1H NMR δ (ppm): 6.56-8.20 (m, 15H), 4.65-4.72 (m, 1H), 4.21 (d, J = 9.9 Hz, 1H), 3.41-3.49 (m, 1H), 3.16 (d, J = 18.7 Hz, 1H), 2.73-2.79 (m, 1H), 2.67 (d, J = 18.7 Hz, 2H), 2.18-2.25 (m, 2H), 2.00-2.07 (m, 1H), 1.85-1.88 (m, 1H);

13

C NMR δ 202.2, 177.7, 172.8, 141.8, 134.9, 133.9, 131.9,


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131.8, 130.8, 130.4, 128.4, 128.0, 127.8, 127.7, 125.6, 124.5, 122.0, 121.6, 80.5, 68.3, 64.5, 57.3, 47.6, 35.0, 29.9, 26.3; IR ν 1712, 1778 cm-1; Anal. Calcd. For C33H25BrN2O3: C, 68.64; H, 4.36; N, 4.85; found: C, 68.53; H, 4.45; N, 4.79. General procedure for the preparation of piperazines 8 and 9 A mixture of acenaphthenequinone 1b (0.5 mmol), L-proline 2 (0.5 mmol) was refluxed in methanol (10 mL) for 3h. After completion of the reaction, as monitored from TLC, the solvent was removed under reduced pressure and residue was chromatographed on silica gel employing ethylacetate-cyclohexane (1:9 v/v) as eluent to obtain the pure products 8 and 9. Spiro[2',3]-bis-(acenaphthene-1’-one)perhydrodipyrrolo[1,2-a :1,2-d]-pyrazine 8 Orange solid (137 mg, 90%); mp = 234-235 °C; 1H NMR δ (ppm): 7.16-7.67 (m, 12H), 3.90 (m, 2H), 2.59-2.64 (m, 2H), 2.12-2.20 (m, 2H), 1.96-2.00 (m, 2H), 1.58-1.83 (m, 6H);

13

C

NMR δ 206.4, 140.7, 136.1, 133.4, 129.9, 129.4, 127.1, 126.9, 124.0, 122.6, 118.6, 71.6, 59.8, 46.9, 27.1, 20.6; IR ν 1708, 1177 cm-1; Anal. Calcd. For C32H26N2O2: C, 81.68; H, 5.57; N, 5.95; found: C, 81.60; H, 5.64; N, 5.90. Spiro[2',5]-bis-(acenaphthene-1’-one)perhydrodipyrrolo[1,2-a :1,2-d]-pyrazine 9 Yellow solid (74 mg, 90%); mp = 244-245 °C;1H NMR δ (ppm): 7.16-7.67 (m, 12H), 3.90 (m, 2H), 2.59-2.64 (m, 2H), 2.12-2.20 (m, 2H), 1.96-2.00 (m, 2H), 1.58-1.83 (m, 6H);

13

C

NMR δ 206.4, 140.7, 136.1, 133.4, 129.9, 129.4, 127.1, 126.9, 124.0, 122.6, 118.6, 71.6, 59.8, 46.9, 27.1, 20.6; IR ν 1715, 1170 cm-1; Anal. Calcd. For C32H26N2O2: C, 81.68; H, 5.57; N, 5.95; found: C, 81.73; H, 5.51; N, 6.04.

DFT calculations The geometric optimizations of all reactants, transition states and products were performed using the B3LYP functional and the 6-31G(d,p)32 basis set in the Gaussian 0933 environment,



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by using the Berny analytical gradient method.34 The global electrophilicity index, ω, was calculated following the expression,25,

26

ω = (µ2/2η), where µ is the electronic chemical

potential, µ = (EH + EL)/2, and η is the chemical hardness, η = (EL - EH). The Fukui condensed functions have been calculated from local populations found from single point calculations carried out on reduced, neutral and oxidized forms with geometries optimized for neutral species. Characterizations have been performed under the same level of calculation. Vibrational analysis has been performed for all the stationary points. Transition states are characterized by a single negative imaginary frequency. For all transition state structures, the intrinsic reaction coordinate (IRC)35 calculation, using the Hessian based predictor–corrector (HPC) method,36 was performed to ascertain that each transition state connected the expected reactants and products. Thermal corrections were computed from unscaled frequencies for a standard state of 298.15 K and 1 atm in gas phase, and within the harmonic approximation.

X-Ray Crystallography Diffraction data for crystal structure determinations of 4e, 5d and 7a were collected on an Oxford Diffraction Xcalibur Sapphire 3 diffractometer at 173 K. The following softwares were used: data collection: CrysAlis CCD (Oxford Diffraction, 2006); cell refinement, data reduction andabsorption correction (multi-scan): CrysAlis RED (Oxford Diffraction, 2006). Intensity data for 6d were recorded on a Nonius Kappa Apex II diffractometer at 115 K. Softwares used for data collection and reduction: SAINT V8.27B (Bruker AXS Inc., 2012); absorption correction: multi-scan (SADABS V2012/1, Bruker AXS Inc., 2012). All four structures were solved by applying direct methods (ShelXS)37 and refined with ShelXL37 using the Olex2 package.38 All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were refined in a riding model with isotropic temperature parameters Uiso(H) = parameters Uiso(H) set to 1.2 times Uiso of heavy atoms bearing them for ternary CH,


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secondary CH2, aromatic CH and amide NH groups. Compound 5d showed an ambiguous Flack parameter of 0.38(3) indicating an inversion twin, therefore it was refined using TWIN in refinement. The crystal data, data collection and structure refinement of compounds 4e, 5d, 6d and 8 are presented in Table S3 (in ESI). Additional crystallographic details can be obtained free of charge

from

the

Cambridge

Crystallographic

Data

Centre

via

www.ccdc.cam.ac.uk/datarequest/cif; CCDC numbers: 1405446 for 4e, 1405447 for 5d, 1405448 for 6d and 1405449 for 8.

ASSOCIATED CONTENT Supporting Information Additional details on computations, including total energies and Cartesian Coordinates for computed structures and transition states structures. 1H NMR and

13

C NMR spectra for all

compounds. 2D NOESY spectra for compounds 4d, 5d and 6d. ORTEP plots of 4e, 5d, 6d and 8 and presentations of the hydrogen bonding occurring in 4e, 5d, and 6d. This material is available free of charge via the Internet at http://pubs.acs.org/.

AUTHOR INFORMATION * e-mail: [email protected] ; phone: +216 98676187

ACKNOWLEDGMENT Computations have been made available thanks to the Calcul Quebec, and Compute Canada. MK, MMK and CS thank the CNRS and the DFG for funding.



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REFERENCES (1) Hartmann, T.; Witte, L. Chemistry, Biology and Chemoecology of Pyrrolizidine Alkaloids. In Alkaloids: Chemical and Biological Perspectives. Pelletier (ed.). Pergamon Press, 1995;

Vol. 9. (2) Liddel, J. R. Nat Prod Rep. 1996, 13, 187 and 653. (3) (a) Karthikeyan, S. V.; Bala, B. D.; Raja, V.P.; Perumal, S.; Yogeeswari, P.; Sriram, D. A. Bioorg. Med. Chem. Lett. 2010, 20, 350–353. (b) Dandia, A.; Jain, A. K.; Laxkar, A. K. RSC Adv. 2013, 3, 8422–8430.

(4) (a) Girgis, A. S. Eur. J. Med. Chem. 2009, 44, 91–100. (b) Yu, B.; Yu, D.Q.; Liu, H. M. Eur. J. Med. Chem. 2014, in press, 162.

(5) Periyasami, G.; Raghunathan, R.; Surendiran, G.; Mathivanan, N. Bioorg. Med. Chem. Lett. 2008, 18, 2342–23425. Bhaskar, G.; Arun, Y.; Balachandran, C.; Saikumar, C.; Perumal,

P. T. Eur. J. Med. Chem. 2012, 51, 79–91. (6) (a) Mhaske, P. C.; Shelke, S. H.; Jadhav, R. P.; Raundal, H. N.; Patil, S. V.; Patil, A. A.; Bobade, V. D. J. Heterocyclic Chem. 2010, 47, 1415–1420. (b) Prasanna, P.; Balamurugan, K.; Perumal, S.; Yogeeswari, P.; Sriram, D. Eur. J. Med. Chem. 2010, 45, 5653–5661. (7) (a) Raj, A. A.; Raghunathan, R.; Sridevi Kumari, M. R.; Raman, N. Bioorg. Med. Chem. 2003, 11, 407–419. (b) Thangamani, A. Eur. J. Med. Chem. 2010, 45, 6120–6126. (8) (a) Jiang, T.; Kuhen, K.L.; Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.; Wu, T.Y.; He, Y. Design, Bioorg. Med. Chem. Lett. 2006, 16, 2105–2108. (9) García Prado, E.; García Gimenez, M. D.; De la Puerta Vázquez, R.; Espartero Sánchez, J. L.; Saenz Rodríguez, M. T. Phytomedicine 2007, 14, 280–284. (10) (a) Cui, C. -B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52, 12651–12666. (b) Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000, 122, 5666–5667. (c) Meyers, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42, 694–696.


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